Cocaine abuse remains a significant public health problem for the world, and particularly the United States. In 2007 over 2.1 million Americans reported cocaine use in the past month, and over 1.6 million met criteria for cocaine dependence or abuse. However, there is no current FDA approved pharmacological treatment option for cocaine addiction, thus limiting therapeutic approaches. Neurobiological targets derived from animal models have provided, and will continue to provide, a valid platform for more precise pharmacotherapeutic development. Genome wide studies have shown that in the nucleus accumbens (NAc), a brain region critical to the neural reward pathway, the levels of key WNT signaling molecules appear to be affected by cocaine use. This proposal hypothesizes that persistent cocaine exposure modulates the WNT signaling pathway in the NAc through alterations in transcription factor binding and chromatin remodeling. Furthermore, it is hypothesized that these molecular adaptations in turn contribute to the behavioral phenotype that characterizes cocaine addiction. This proposal seeks to more fully characterize this novel regulation-to determine how WNT gene expression levels are altered by cocaine in the NAc with real-time PCR and western blotting, through which mechanisms this regulation occurs with chromatin immunoprecipitation, and finally to determine the functional significance of these changes at the behavioral level with in vivo viral-mediated gene transfer. PUBLIC HEALTH RELEVANCE: Despite the fact that cocaine abuse remains a significant public health problem for the United States, there is no current FDA approved pharmacological treatment option, which limits therapeutic approaches. This study seeks to characterize the role of a ubiquitous cell signaling pathway, the WNT pathway, in the brain's reward region in the context of cocaine use. This will hopefully serve to improve understanding of addiction pathophysiology and thus contribute to more precise and educated pharmacotherapeutic development.